The catabolism of antitumor alkaloids found in Catharanthus roseus will be investigated as a search for new antitumor drugs, as an aid to elucidating the structure-activity relationships among the known oncolytic alkaloids from the plant, and as a research thrust into the currently obscure area of secondary natural product catabolism and function. Full structural characterization of the catabolites and eventual testing of their oncolytic activity will be done to construct a catabolic pathway for the Catharanthus alkaloids and to examine structure-activity relationships. The biosynthesis of the dimeric, indole-indoline alkaloids of C. roseus will be investigated on the basis of the incorporation of tryptophan and stereospecifically labeled loganin by radiochemical labeling techniques. Depending on the initial results, possible syntheses of suspected intermediates in the biosynthesis and testing of their actual role may be sought. The sequential biosynthetic interrelationship of these alkaloids will also be examined by means of C-14 CO2 labeling studies. The biosynthesis of camptothecin, an antitumor alkaloid from Camptotheca acuminata, will be investigated via a hypothesis adapted from work of E. Wenkert. Tryptophan, loganin, vincoside, and other putative precursors, including the quinoline analogs of vincoside lactam will be validated or eliminated as constituents of the biosynthetic pathway to camptothecin. Stereochemical requirements of the intermediates will be ascertained. Analog synthesis of camptothecin will be undertaken in an attempt to find a less toxic and/or more potent derivative that might be a clinically useful antitumor drug. The analogs will be used to examine the mechanism of action of camptothecin. BIBLIOGRAPHIC REFERENCES: A. H. Heckendorf, K. C. Mattes, C. R. Hutchinson, E. W. Hagaman, and E. Wenkert, "Stereochemistry and Conformation of Biogenetic Procursors of Indole Alkaloids", J. Org. Chem., 41, XXXX (1976). P. E. Daddona, J. L. Wright, and C. R. Hutchinson, "Alkaloid Catabolism and Mobilization in Catharanthus Roseus", Phytochemistry , 15, XXXX (1976).